After taking a new look at the treatments traditionally offered to rectal cancer patients, scientists say their “de-escalation” trial suggests these people can do just as well without radiation therapy, meaning tens of thousands of cancer sufferers could have the option to skip a treatment that can have serious side effects.
The results, revealed at the annual meeting of the American Society of Clinical Oncology and in a paper in the New England Journal of Medicine, could give more than thousands of patients the option to rely on only chemotherapy and surgery to treat their illness.
For decades, it was typical to use pelvic radiation, reports The New York Times. But not only can this cause additional cancers, it also puts women into immediate menopause and damages sexual function in both men and women. It also can injure the bowel, causing issues like chronic diarrhoea, while patients risk pelvic fractures.
Yet radiation treatment, the study found, did not improve outcomes. After a median follow-up of five years, there was no difference in key measures – the length of survival with no signs that the cancer has returned, and overall survival – between the group that had received the treatment and the group that had not. And, after 18 months, there was no difference between the two groups in quality of life.
Rectal cancer affects 47 500 people per year in the United States (although the class of the disease in the study affects about 25 000 Americans annually).
For colon and rectal cancer specialists, the results of this latest trial can transform patients’ lives, said Dr Kimmie Ng, a co-director of the colon and rectal cancer centre at the Dana-Farber Cancer Institute, who was not involved in the study.
“Now, especially, with patients skewing younger and younger, do they actually need radiation?” she asked. “Can we choose which patients can get away without this extremely toxic treatment that can lead to lifelong consequences, like infertility and sexual dysfunction?”
The trial focused on patients whose tumors had spread to lymph nodes or tissues around the bowel, but not to other organs. That subset of patients, whose cancer is deemed locally advanced, constitutes about half of the 800 000 newly diagnosed rectal cancer patients worldwide.
In the study, 1 194 patients were randomly assigned to one of two groups, one receiving the standard treatment, a long and arduous ordeal that began with radiation, followed by surgery, and then, after the patients recovered from surgery, chemotherapy at their doctor’s discretion.
The other group received the experimental treatment: chemotherapy first, followed by surgery. At their doctor’s discretion, another round of chemotherapy could be given. These patients had radiation only if the initial chemotherapy failed to shrink their tumours – which happened just 9% of the time.
Not all patients were eligible for the trial. The researchers excluded those whose tumours seemed too dangerous for only chemotherapy and surgery.
Dr Deborah Schrag of Memorial Sloan Kettering Cancer Centre, who led the trial, said those patients received the standard radiation treatment.
Schrag and Dr Ethan Basch of the University of North Carolina at Chapel Hill also asked patients to report on their quality of life. How much pain were they in? How much fatigue did they have? How much diarrhoea? Did they have neuropathy – hands and feet that tingle and lose feeling? How were their sex lives? Did symptoms resolve? How long did it take for symptoms to wane?
“When 80% of patients are alive after five years, we want to say they are living well,” Schrag said.
The two groups had different symptoms at different times. But after two years, there was a trend toward a better quality of life in the group that received chemotherapy. And on one measure – male and female sexual function – the chemotherapy group clearly fared better.
Early on, those on chemotherapy without radiation had more nausea, vomiting and fatigue. A year later, Basch said, the radiation group was suffering more, with fatigue, impaired sexual function and neuropathy.
“Now patients who are trying to decide if they want radiation or chemotherapy can see how those in the trial fared and decide which symptoms matter most to them,” he said.
This sort of clinical trial is very challenging. It is known as a de-escalation study because it takes away a standard treatment to see if it’s needed. No company will pay for such a trial.
And, as the rectal cancer researchers discovered, even the National Institutes of Health (NIH) was hesitant to support their study, arguing that the investigators would never persuade enough doctors to enrol patients and that even if they did, too few patients would agree to join, fearing it would risk their health.
While the NIH eventually agreed to sponsor the study, its misgivings were justified – it took the researchers eight years to enrol 1 194 patients at 200 medical centres.
“It was brutally difficult,” said Dr Alan Venook of the University of California-San Francisco, who helped design the study.
Schrag said it required “unbelievably courageous patients” and doctors who were confident the study was ethical.
Radiation has long been used as a way to prevent the recurrence of rectal cancer. Chemotherapy and surgery often controlled the disease, but all too often, cancer emerged again in the pelvis. Horrific effects could follow – tumours that eroded the bladder, the uterus, the vagina.
The addition of radiation addressed recurrence in the pelvis but caused its own set of problems.
As years went by, some researchers began to wonder if radiation was still necessary. Chemotherapy, surgery and medical imaging had improved, and patients were being diagnosed earlier, before their cancer was as advanced.
Schrag and her colleagues tested the idea of eliminating radiation with a pilot study with what she called “30 courageous patients”. The results were encouraging enough to make the case for a broader study.
Venook said the study was a triumph in more ways than one.
“In rectal cancer, there are schools of thought,” he said. “People think they know what the right answer is.”
Study details
Preoperative treatment of locally advanced rectal cancer
Deborah Schrag, Qian Shi, Martin Weiser, Marc Gollub, Leonard Saltz, Benjamin Musher, Joel Goldberg, Tareq Al Baghdadi, Karyn Goodman, Robert McWilliams, Jeffrey Farma, Thomas George, et al.
Published in The New England Journal of Medicine on 4 June 2023
Abstract
Background
Pelvic radiation plus sensitising chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.
Methods
We conducted a multicentre, unblinded, non-inferiority, randomised trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumour decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Non-inferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.
Results
From June 2012 through December 2018, a total of 1194 patients underwent randomisation and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was non-inferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P=0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.
Conclusions
In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was non-inferior to preoperative chemoradiotherapy with respect to disease-free survival.
NEJM article – Preoperative treatment of locally advanced rectal cancer (Open access)
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